Non-alcoholic fatty liver disease (NAFLD) is the most common cause of end-stage liver disease in the developed world;two-thirds of the obese develop NAFLD and are at risk for developing cirrhosis, end-stage liver disease, and hepatocellular carcinoma. However, because its pathogenesis is poorly defined, there are currently no methods to predict, prevent or treat NAFLD progression. Our long-term objective is to identify genetic variants that influence the development and progression of NAFLD and to elucidate the molecular and cellular mechanisms by which they act. In a recent genome wide association study (GWAS) meta-analysis published by our group, a novel association between NAFLD and a single nucleotide polymorphism (SNP), rs2228603 was discovered. This non-synonymous SNP converts serine to proline at position 92 of the neurocan (NCAN) gene. The applicant replicated this association in an independent cohort of morbidly obese patients and discovered that this variant was associated with liver inflammation and fibrosis;this indicates a more advanced stage of NAFLD. Neurocan is a chondroitin sulfate proteoglycan. Although initially observed in the central nervous system, our preliminary data indicate that NCAN is also expressed in liver. We hypothesize that rs2228603 or a SNP in linkage disequilibrium is the most likely functional variant that promotes NAFLD. To test this hypothesis, we will fine map this locus to exclude other causative variants. Then, we will begin to functionally characterize NCAN and its variant. Two Specific Aims will achieve these goals: Aim 1 Use fine mapping to narrow the region surrounding SNP rs2228603 on chromosome 19 to identify the most likely functional variant contributing to increased risk for hepatic steatosis. Aim 2 Determine the association between NCAN expression, the most likely functional SNP variant and NAFLD severity. Successful completion of the proposed project will identify a novel gene and functional variant that influences the development of NAFLD. These insights may lead to novel targets and strategies for prevention and treatment. In addition, this research project, coupled with a structured career development plan conducted under the guidance of exceptional mentors and a strong institutional commitment, will provide Dr. Gorden with an outstanding opportunity to develop a multidisciplinary patient-oriented research focus and the skills and productivity to launch an independent academic research career. PUBLIC HEALTH RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of end-stage liver disease in the developed world. We propose to use a comprehensive multi-faceted approach to further characterize NCAN, a novel gene discovered in our group's meta-GWAS, and to determine the mechanism whereby it affects NAFLD. This research may lead to novel targets and strategies for prevention and treatment of NAFLD.